BRAF V600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells

Toshinori Sueda; Daisuke Sakai; Koichi Kawamoto; Masamitsu Konno; Naohiro Nishida; Jun Koseki; Hugh Colvin; Hidekazu Takahashi; Naotsugu Haraguchi; Junichi Nishimura; Taishi Hata; Ichiro Takemasa; Tsunekazu Mizushima; Hirofumi Yamamoto; Taroh Satoh; Yuichiro Doki; Masaki Mori; Hideshi Ishii

doi:10.1038/srep18949

BRAF V600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells

Sci Rep. 2016 Jan 11:6:18949. doi: 10.1038/srep18949.

Authors

Toshinori Sueda^{1

2}, Daisuke Sakai¹, Koichi Kawamoto², Masamitsu Konno¹, Naohiro Nishida¹, Jun Koseki³, Hugh Colvin^{1

2

3}, Hidekazu Takahashi², Naotsugu Haraguchi², Junichi Nishimura², Taishi Hata², Ichiro Takemasa², Tsunekazu Mizushima², Hirofumi Yamamoto⁴, Taroh Satoh¹, Yuichiro Doki^{1

2

3}, Masaki Mori^{1

2

3}, Hideshi Ishii^{1

3}

Affiliations

¹ Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
² Department of Gastrointestinal Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
³ Department of Cancer Profiling Discovery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁴ Department of Molecular Pathology, Osaka University Graduate School of Medicine and Health Science, 1-7, Yamadaoka, Suita, Osaka, 565-0871, Japan.

Abstract

Although BRAF(V600E) mutation is associated with adverse clinical outcomes in patients with colorectal cancer (CRC), response and resistance mechanisms for therapeutic BRAF(V600E) inhibitors remains poorly understood. In the present study, we demonstrate that selective BRAF(V600E) inhibition activates AMP-activated protein kinase (AMPK), which induces autophagy as a mechanism of therapeutic resistance in human cancers. The present data show AMPK-dependent cytoprotective roles of autophagy under conditions of therapeutic BRAF(V600E) inhibition, and AMPK was negatively correlated with BRAF(V600E)-dependent activation of MEK-ERK-RSK signaling and positively correlated with unc-51-like kinase 1 (ULK1), a key initiator of autophagy. Furthermore, selective BRAF(V600E) inhibition and concomitant suppression of autophagy led to the induction of apoptosis. Taken together, present experiments indicate that AMPK plays a role in the survival of BRAF(V600E) CRC cells by selective inhibition and suggest that the control of autophagy contributes to overcome the chemoresistance of BRAF(V600E) CRC cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / genetics*
AMP-Activated Protein Kinases / metabolism
Animals
Antineoplastic Agents / pharmacology*
Autophagy
Caco-2 Cells
Cell Line, Tumor
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Gene Expression Regulation, Neoplastic*
HT29 Cells
Humans
Indoles / pharmacology
Injections, Subcutaneous
MAP Kinase Kinase Kinases / genetics
MAP Kinase Kinase Kinases / metabolism
MAP Kinase Signaling System
Mice
Mice, Inbred BALB C
Mice, Nude
Mutation
Proto-Oncogene Proteins B-raf / antagonists & inhibitors
Proto-Oncogene Proteins B-raf / genetics*
Proto-Oncogene Proteins B-raf / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Sulfonamides / pharmacology
Vemurafenib
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Indoles
PLX 4720
RNA, Small Interfering
Sulfonamides
Vemurafenib
BRAF protein, human
Proto-Oncogene Proteins B-raf
Extracellular Signal-Regulated MAP Kinases
MAP Kinase Kinase Kinases
AMP-Activated Protein Kinases